Citation: Kenji Chiba, Yasuhiro Maeda, Noriyasu Seki, Hirotoshi Kataoka, Kunio Sugahara. Role of sphingosine 1-phosphate (S1P) and effects of fingolimod, an S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases[J]. AIMS Molecular Science, 2014, 1(4): 162-182. doi: 10.3934/molsci.2014.4.162
| [1] | Vera Reitsema, Hjalmar Bouma, Jan Willem Kok . Sphingosine-1-phosphate transport and its role in immunology. AIMS Molecular Science, 2014, 1(4): 183-201. doi: 10.3934/molsci.2014.4.183 |
| [2] | Andrew V. Nguyen, Yuan-Yuan Wu, Elaine Y. Lin . The regulatory function of sphingosine-1-phosphate signaling axis on regulatory T cells in colorectal cancer. AIMS Molecular Science, 2015, 1(1): 34-47. doi: 10.3934/molsci.2015.1.34 |
| [3] | Dimitra Beroukas, Maurice Selhorst, Stuart M. Pitson, Dusan Matusica, Ian L. Gibbins, Michaela Kress, Rainer V. Haberberger . Sphingosine kinase 1 in murine dorsal root ganglia. AIMS Molecular Science, 2015, 1(1): 22-33. doi: 10.3934/molsci.2015.1.22 |
| [4] | J.R. Calvo, M.D. Maldonado . The role of melatonin in autoimmune and atopic diseases. AIMS Molecular Science, 2016, 3(2): 158-186. doi: 10.3934/molsci.2016.2.158 |
| [5] | Amena W. Smith, Swapan K. Ray, Arabinda Das, Kenkichi Nozaki, Baerbel Rohrer, Naren L. Banik . Calpain inhibition as a possible new therapeutic target in multiple sclerosis. AIMS Molecular Science, 2017, 4(4): 446-462. doi: 10.3934/molsci.2017.4.446 |
| [6] | Maria Kristina Parr, Anna Müller-Schöll . Pharmacology of doping agents—mechanisms promoting muscle hypertrophy. AIMS Molecular Science, 2018, 5(2): 131-159. doi: 10.3934/molsci.2018.2.131 |
| [7] | Irene M. Waita, Atunga Nyachieo, Daniel Chai, Samson Muuo, Naomi Maina, Daniel Kariuki, Cleophas M. Kyama . Genetic polymorphisms in eostrogen and progesterone receptor genes in Papio anubis induced with endometriosis during early stage of the disease. AIMS Molecular Science, 2021, 8(1): 86-97. doi: 10.3934/molsci.2021007 |
| [8] | Fazle Khuda, Nur Najmi Mohamad Anuar, Badiah Baharin, Nurrul Shaqinah Nasruddin . A mini review on the associations of matrix metalloproteinases (MMPs) -1, -8, -13 with periodontal disease. AIMS Molecular Science, 2021, 8(1): 13-31. doi: 10.3934/molsci.2021002 |
| [9] | Jin-Yih Low, Helen D. Nicholson . The up-stream regulation of polymerase-1 and transcript release factor(PTRF/Cavin-1) in prostate cancer: an epigenetic analysis. AIMS Molecular Science, 2016, 3(3): 466-478. doi: 10.3934/molsci.2016.3.466 |
| [10] | Seidu A. Richard, Wu Min, Zhaoliang Su, Hua-Xi Xu . Epochal neuroinflammatory role of high mobility group box 1 in central nervous system diseases. AIMS Molecular Science, 2017, 4(2): 185-218. doi: 10.3934/molsci.2017.2.185 |
An immunosuppressivenatural product, (2S,3R,4R)-(E)-2-amino-3, 4-dihydroxy-2-(hydroxy- methyl)-14-oxoeicos-6-enoic acid, (myriocin, ISP-I) (Figure 1) was isolated from cultures of Isaria sinclairii, a type of entomopathogenic fungus that is an "eternal youth" nostrum in traditional Chinese medicine [1]. Myriocininhibits antigen-stimulated T cell proliferation in vitro and prolongs rat skin allograft survival for several days in vivo; however this compound is a rather complicated D-amino acid with three successive asymmetric centers and higher dosages induced strong toxicity in vivo [1]. Simplification of the structure of myriocin wasconducted by the elimination of chiral centers and removal of the side chain functionalities [2,3]. These chemicalmodifications of myriocin led to a novel compound, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1, 3-diolhydrochloride(FTY720, fingolimod hydrochloride) (Figure 1) with more potent immunosuppressiveactivity and less toxicity when compared to myriocin [4,5,6,7,8]. After several years, it has been shown that myriocin inhibitsserinepalmitoyltransferase, the first enzyme in sphingolipid biosynthesis whereas FTY720 showed no effect, suggesting distinct mechanisms of action for these two compounds [5].
Figure 1. Chemical structures of myriocin and FTY720.
FTY720 (0.1 mg/kg or higher, orally) shows a potent immunosuppressive activity in experimental allograft models and various autoimmune disease models including: experimental autoimmune encephalomyelitis (EAE), adjuvant- or collagen-induced arthritis in rats and mice, and lupus nephritis in MRL/lpr mice [9,10,11,12,13]. However, unlike cyclosporin A (CsA), FTY720 does not impair lymphocyte functions such as T cell activation and production of interleukin (IL)-2 by T cells[14,15,16]. The most striking feature of FTY720 is the induction of a marked decrease in the number of peripheral blood lymphocytes (PBL) at doses that show immunosuppressive effects [9,14]. When FTY720 at an oral dose of 0.1 mg/kg or higher is given to rats or mice, the number of lymphocytes in the peripheral blood and thoracic duct lymph decrease markedly whereas the number of lymphocytes in the secondary lymphoid organs (SLO)increases significantly [14]. Intravenous transfusion of fluorescein-labeled lymphocytes into rats reveals that the labeled lymphocytes are accumulated in the SLO by FTY720 [14]. These findings strongly suggest that FTY720 induces sequestration of circulating mature lymphocytes in the SLO, thereby reducing the number of PBL and T cell infiltration into inflammatory sites [14,15,16]. Accordingly, the sequestration of circulating lymphocytes is presumed be the main mechanism of immunosuppressive activity of FTY720.
Throughout the analyses of the molecular mechanism of FTY720, it has been highlighted that a pleiotropic lysophospholipid mediator, sphingosine 1-phosphate (S1P), and its receptor 1 (S1P1) play an important role in lymphocyte circulation between the blood, SLO, and lymph[17,18,19]. S1P is synthesized by phosphorylation of sphingosine by two isoforms of sphingosine kinase (SPHK1 and SPHK2) [20,21]. S1P acts as ahighaffinity agonistto five related G-protein-coupled receptors, termed S1P1, S1P2, S1P3, S1P4, and S1P5 [22,23] and regulates various cellular processes that are important for immune responses and inflammation [24,25]. Since FTY720 has a structure closely related to sphingosine, it has been demonstrated that FTY720 iseffectively converted to an active metabolite, FTY720 phosphate (FTY720-P, the (S)-enantiomer) by SPHKs [26]. Although FTY720-P is a high affinity agonist at 4 types of S1P receptors (S1P1, S1P3, S1P4, and S1P5) [17,18], FTY720-P induces down-regulation of S1P1 and acts as a functional antagonist at S1P1 [19,27,28,29]. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO and reducesthe number of PBL. This paper summarizes the current understanding of the S1P-S1P1 axis in the immune system based on the analyses of S1P1 functional antagonismby FTY720 and discusses the feasibility of the S1P-S1P1 axis as a therapeutic target for the treatment of autoimmune diseases.
Circulation of mature lymphocytes between the blood, SLO, and lymph plays a central role in the establishment of the immune response to foreign antigens. Homing of lymphocytes from blood into the SLO is highly dependent on the interaction between the homing chemokines: CC-chemokine ligand (CCL) 19, CCL21, CXC-chemokine ligand (CXCL) 12, and CXCL13, and their receptors: CCR7, CXCR4, and CXCR5 [30]. On the other hand the reverse pharmacological approaches to define the molecular target of FTY720 have clarified that the S1P-S1P1 axis plays an essential role in lymphocyte circulation [19,30].
S1P is a potent biologically active sphingolipid metabolite which is primarily generated by the phosphorylation of intracellular sphingosine by SPHK1 at the plasma membrane, and SPHK2 at the endoplasmic reticulum, mitochondria and nucleus in most cells [20,21]. S1P, in turn, can be exported by the ATP-binding cassette (ABC) family of transporters [31] or by the S1P transporter spinster homologue 2 (SPNS2) [32] to activate S1P receptors in autocrine and/or paracrine manners. S1P stimulates multiple signaling pathways resulting in calcium mobilization from intracellular stores, polymerization of actin, chemotaxis/migration, and escape from apoptosis; in addition to regulation of diverse cellular processes that are important for immune responses and inflammation [24,25]. In most tissues, including the SLO, S1P levels are kept extremely low (< 10 nM), because S1P is irreversibly degraded by intracellular S1P lyase or dephosphorylated by S1P phosphatase [33,34,35]. Conversely, levels of S1P in the blood are in the μM range. Similarly, significantly high amounts (hundred nMrange) of S1P are found in the lymph [36,37]. These data indicate that a concentration gradient of S1P is existingbetween blood-lymph and SLO [30,38] (Figure 2). Plasma S1P is tightly associated with albumin and lipoproteins, particularly high-density lipoprotein. Although S1P is released by platelets ininflammation, the major source of plasma S1P is red blood cells whereas S1P in the lymph is mainly produced by endothelium [36]. Excessive production of S1P can be induced at inflammatory sites as a result of cell activation by pro-inflammatory cytokines. The S1P gradient between blood-lymph and SLO, as well as over production of S1P at inflammatory sites, appears to play an important role in regulation of circulation and trafficking of lymphocytes(Figure 2).
Figure 2. Role of the S1P-S1P1 axis in lymphocyte egress from the SLO. (A) S1P is generated from sphingosine by sphingosine kinases, released by the S1P transporter, and binds to the S1P1 receptor. (B) Reacquisition of lymphocytic S1P1 expression in low S1P condition plays an important role in lymphocyte egress from the SLO to lymph.
S1P binds with highaffinities to five related G-protein-coupled receptors, termed S1P1, S1P2, S1P3, S1P4, and S1P5 [22,23]. S1P1, S1P2, and S1P3receptors are widely expressed in the immune, cardiovascular, and central nervous systems. S1P4 is selectively expressed in lymphoid tissues and lungs whereas S1P5 is expressed in natural killer cells, the spleen, and white matter tracts of the central nervous system. The expression of S1P1 mRNA in CD4 T cells is markedly higher than the other S1P receptors, suggesting that S1P1 is the dominant receptor on lymphocytes [19,27,28,29]. It has been reported that lymphocytic S1P1 plays an essential role in lymphocyte circulation, particularly in lymphocyte egress from the SLO and thymus; because mature T cells are unable to exit the SLO and there are no T cells in the periphery in mice whose hematopoietic cells lack S1P1 receptors [19].
S1P (10 to 100 nM) can induce migration of lymphocytes [12,19,28], and lymphocytes from S1P1-deficient miceshowed extremely low levels of migration toward S1P, suggesting that lymphocyte migration is S1P1-dependent [19]. S1P1-dependent migratoryresponsiveness is suggested to be up-regulated in lymphocytes before exit from the SLO, whereas S1P1 is down-regulated during peripheral lymphocyte activation, and this is associated with retention of lymphocytes in the SLO [19,38]. Because S1P1surface expression on lymphocytes is highly dependent on the extracellular concentration of S1P, S1P1 on lymphocytes is down-regulated in the blood and lymph, and up-regulated in the SLO. Consequently, it is widely accepted that cyclical modulation of S1P1surface expression on circulating lymphocytes by S1P contributes to establishing their transit time in the SLO [38] (Figure 2).
Using reverse pharmacological approaches to clarify the mechanism of action of FTY720, it has been demonstrated that, like sphingosine, FTY720 is a substrate for SPHK1 and SPHK2 and is converted to FTY720-P [26]. The (S)-enantiomer of FTY720-P binds to four subtypes of S1P receptors (S1P1, S1P3, S1P4, and S1P5) but not S1P2, and acts as a high affinity agonist at these receptors whereas FTY720, up to 10000 nM, shows no binding toS1P receptors [17,18,39]. After oral or intravenous FTY720 administration, the plasma concentration of FTY720-P was 2 to 6 times higher than FTY720 [17]. In Chinese hamster ovary (CHO) cells stably expressing human S1P1, S1P and FTY720-P can induce phosphorylation of extracellular signal regulated kinase 1/2 and subsequentlyinduce internalization of S1P1 from the cell surface [19,28,40].
Internalization of S1P1 by S1P is transient and reversible, as internalized S1P1 is recycled and re-expressed on the cell surface within several hours after S1P stimulation (Figure 2). On the other hand, FTY720-P strongly induceslong-lasting down-regulation of S1P1 on the cell surface by internalization and degradation of this receptor [27,28,40,41] (Figure 3).Consequently, FTY720 treatment down-regulates S1P1, pharmacologically creating a temporary S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration into the SLO. The down-regulation of S1P1 by FTY720-P appears to be maintained longer than down-regulation by S1P because FTY720-P, but not S1P, induces degradation of internalized S1P1 [41]. The pretreatment with FTY720-P effectively inhibits the migration of CD4 T cells toward S1P [12,19,28]. Based on these results, it is highly likely that FTY720-P acts as a functional antagonist at S1P1 by internalization and degradation of this receptor, reducing S1P responsiveness of lymphocytes, and inhibiting S1P1-dependent lymphocyte egress from the SLO (Figure 3).
Figure 3. FTY720-P converted from FTY720 acts as a functional antagonist at lymphocytic S1P1. (A) FTY720-P is converted from FTY720 by sphingosine kinases, binds S1P1 receptor, and induces internalization and degradation of S1P1. (B) FTY720-P inhibits S1P1-dependent lymphocyte egress from the SLO.
Intrathymic T cell development is critical for immune surveillance and immune effector function [42,43]. Thymocytes undergo a series of defined developmental stages in the thymus. After entering the thymus, early thymic progenitor cells differentiate into T cell receptor-expressing CD4, and CD8 double-positive (DP) thymocytes in the cortex. Then, CD4, CD8 DP thymocytes mature into CD4 single-positive (SP) and CD8 SP thymocytes in the medulla [42,43]. Mature CD4 SP and CD8 SP thymocytes are shown to be located in the perivascular spaces (PVS) surrounding large blood vessels at the cortico-medullary junction and the medulla; and exit from the thymus through the PVS and blood vessels in mice [44,45,46,47] (Figure 4). Therefore, the PVS are thought to be a transit pathway for mature thymocytes to emigrate from the thymus. It has been widely accepted that higher amounts of S1P in the blood can stimulate S1P1 expression on mature thymocytes to induce migration and egress from the thymus where S1P concentrations are typically low [48]. As reported previously, FTY720 induces accumulation of CD4 SP and CD8 SP thymocytes in the thymic medulla in mice [49]. Intrathymic injection of fluorescein-labeled thymocytes to mice revealed that FTY720 inhibits egress of mature thymocytes from the thymus to blood [49].
Figure 4. Role of S1P-S1P1 axis in thymic egress. (A) CD4- or CD8-single positive (SP) thymocytes express S1P1 in thymic medulla and exit from thymus via PVS. (B) S1P1 expression is predominantly found in the thymic medulla in mice. FTY720 (1 mg/kg, orally) induces down-regulation of S1P1 in the thymus.
In addition, it is demonstrated that FTY720 inducessignificant accumulation of CD62Lhigh CD69low mature SP thymocytes in the thymic medulla [50]. Immunohistochemical staining using anti-S1P1 antibody revealed that S1P1 is predominantly expressed on thymocytes in the thymic medulla and is down-regulated strongly and rapidly after FTY720 administration [50] (Figure 4). Since FTY720-P internalizes and degrades S1P1 [41], it is likely that FTY720 inhibits the thymic egress by functional antagonism at S1P1. Similarly, the thymic egress is shown to be at extremely low levels in hematopoietic cell- or T cell-specific S1P1knock-out mice [19]. These results indicate that thymic egress is highly dependent on S1P1 expressed on mature thymocytes, especially CD62Lhigh CD69low recent thymic emigrants.
The tissue S1P concentration is maintained at low levels by several S1P-degrading enzymes which are categorized into two classes [51]. The first consists of S1P lyase, which irreversibly cleaves S1P to 2-hexadecenal and phosphoethanolamine; and S1P phosphatases 1 and 2, which dephosphorylate S1P to sphingosine [52]. The second class of S1P-degrading enzymes consists of three phosphatases: lipid phosphate phosphatase (LPP) 1, 2 and 3 [53]. Although S1P lyase resides predominantly in the endoplasmic reticulum, inhibition of S1P lyase activity by 4-deoxypyridoxin (DOP), a vitamin B6 antagonist, or 2-acetyl-4-tetrahydroxy-butylimidazole (THI) causes a marked elevation of extracellular S1P concentration in murine thymus [37]. Because S1P1expression on lymphocytes is highly dependent on the tissue S1P concentration, the treatment with DOP or THI down-regulates S1P1 expression and subsequently induces accumulation of mature thymocytes in the thymus by inhibiting S1P1-dependent thymic egress [37,49]. Consistent with the results obtained by administration of S1P lyase inhibitors to mice, S1P lyase-deficiency in mice shows elevated intrathymic S1P concentration and accumulation of mature thymocytes in the thymus [54]. Consequently, inhibition of S1P1function or disruption of S1P gradients between blood and thymus results in accumulation of mature thymocytes in the thymus because of the missing egress signal. In mice, S1P1 is shown to be expressed in mature CD4 SP or CD8 SP thymocytes by flow cytometry [37,51], whereas S1P lyase is found in the thymic medulla by immunohistochemical staining [55]. Recent immunohistochemical analysis using anti-mouse S1P lyase monoclonal antibody has revealed that S1P lyase is predominantly expressed in non-lymphoid thymic stromal cells in the thymic medulla [50]. In the thymic medullary PVS, S1P lyase was expressed in ER-TR7-positive cells (reticular fibroblasts and pericytes) and CD31-positive vascular endothelial cells [50]. These findings suggest that S1P lyase expressed in the thymic medullary PVS results in low tissue S1P concentration around the vessels and promotes thymic egress via up-regulation of S1P1.
As described above, the reduction of PBL by FTY720 is highly dependent on the presence of the SLO. However, it has been reported that FTY720 (1 to 10 mg/kg) decreases the number of PBL in alymphoplasia (aly/aly) mice lacking SLO [56,57,58,59]. Since FTY720 at concentrations of 4000 nM or higher induces the apoptosis of lymphocytes in vitro [49,50], it has been hypothesized that FTY720 (10 mg/kg) decreases PBL in aly/aly mice by inducing apoptosis in lymphocytes. Conversely, two independent studies have demonstrated that a lower dose of FTY720 (1 mg/kg) can also decrease the number of PBL in aly/aly mice significantly [58,59]. Since the blood level of FTY720 in rats or mice treated with 1 mg/kg is less than 200 nM [12], it would seem to be highly unlikely for FTY720 at 1 mg/kg to induce apoptosis of lymphocytes. Accordingly, the hypothesis that FTY720 induces lymphocyte apoptosis is inadequate for explaining the mechanism through which PBL are decreased by FTY720 in aly/aly mice. Thus, the question arises as to whether PBL are sequestered at unknown sites excluding the SLO when FTY720 is administered to aly/aly mice.
Recently, it has been demonstrated that mature lymphocytes were sequestered in the bone marrow of aly/aly mice after administration of FTY720 (1 mg/kg) [60]. These results imply that the reduction of PBL by FTY720 in aly/aly mice is predominantly due to inhibition of the egress of mature lymphocytes from the bone marrow and not through induction of lymphocyte apoptosis. Consequently, it is highly likely that the S1P-S1P1 axis plays an important role in the egress of mature T cells including antigen-specific Th cells from the bone marrow as well as SLO.
Oral administration of FTY720 is highly effective in EAE, a CD4 T cell-dependent model for multiple sclerosis (MS) [61,62,63,64,65,66]. The development of EAE induced by myelin proteolipid protein (PLP) in SJL/J mice is almost completely prevented by prophylactic treatment with FTY720 orFTY720-P; and infiltration of CD4 T cells into the spinal cord is also decreased [61,62]. When FTY720 (0.1 and 0.3 mg/kg orally) is given after induction of EAE by PLPin SJL/J mice, the relapse of EAE is significantlyinhibited as compared with recombinant mouse IFN-β (10,000 international units (IU)/mouse, subcutaneously); and the infiltration of CD4 T cells are markedly decreased in the spinal cords of EAE mice [62,66]. Similar therapeutic effects by FTY720 are generated in EAE induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice [62,66].
In EAE induced by myelin basic proteinin LEW rats, prophylactic administration of FTY720 (0.1 to 1 mg/kg orally) almost completely prevents the development of EAE symptoms; and therapeutic treatment with FTY720 significantly inhibits the progression of EAE and EAE-associated histological changes in the spinal cord [62]. In EAE induced by MOGin DA rats, prophylactic therapy with FTY720 protects against the emergence of EAE symptoms, neuropathology, and disturbances to visual and somatosensory evoked potentials [63,64]. Moreover, therapeutic treatment with FTY720 markedly reverses paralysis in established EAE and normalizes the electrophysiological responses with decreased demyelination in the CNS [63].
Infiltration of encephalitogenic CD4 T cells, particularly IL-17-expressing helper T cells (Th17 cells)and interferon (IFN)-γ-expressing helper T cells type 1 (Th1 cells) into the CNS plays a critical role in development and progression of EAE in mice [67,68,69]. FTY720 (0.1 mg/kg or higher, orally) significantly inhibits the development of EAE and markedly reduces the infiltration of Th17 and Th1 cells in the spinal cords of EAE mice [66]. On the contrary, the frequency of Th17 and Th1 cells in draining lymph nodes (DLN) is significantly increased by FTY720, suggesting sequestration of myelin antigen-specific Th17 and Th1cells into the DLN [66].
Recent studies demonstrate a role for the S1P-S1P1 axis in DLN lymphocytes for EAE development when C57BL/6 mice are immunized with MOG [70]. S1P responsiveness of DLN lymphocytes was noticeably down-regulated after MOG immunization; and accompanying reacquisition of down-regulated S1P responsiveness in DLN lymphocytes resulted in mice that developed EAE with significant infiltration of Th17 and Th1 cells into the CNS. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th17/Th1 cells from the DLN to the CNS in EAE. Prophylactic administration of FTY720 significantly inhibited EAE development and almost completely prevented infiltration of Th17 and Th1 cells into the CNS [70]. FTY720-P inhibited in vitro migration of Th17 and Th1 cells toward S1P via S1P1 but did not affect production of IL-17/IFN-γ or generation of Th17/Th1 cellsfrom naïve CD4 T cells [70]. Consequently, the prophylactic effects of FTY720 on EAE are likely due to inhibition of S1P1-dependent egress of autoreactive T cells from the DLN.
Therapeutic administration of FTY720 showed significant improvement of EAE induced by immunization with MOG in C57BL/6 mice [62,66] but only induced a partial reduction of T cell infiltration into the CNS, suggesting the involvement of different mechanisms not mediated via lymphocytic S1P1. Recently, it has been strongly suggested that FTY720-P directly acts as a functional antagonist at S1P1 on neural cells, particularly astrocytes [71,72] because astrocytes express S1P1 and FTY720 can distribute into the CNS beyond blood brain barrier [64]. EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P1 on glial fibrillary acidic protein (GFAP)-expressing astrocytes but not on neurons; suggesting that the loss of S1P1 on astrocytes through functional antagonism by FTY720-P is a primary mechanism of FTY720 action [71,72]. Interestingly, S1P can induce production of IL-6, IL-8 and CCL2 in human astrocytic glioma, U373MG cells, and FTY720-P inhibits S1P-induced production of these pro-inflammatory cytokines by down-regulation of S1P1 [73]. These results imply that the S1P-S1P1 axis plays a key role in astrocyte-mediated neuroinflammation.
In other chronic autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), it is widely accepted that infiltration of autoreactive lymphocytes in specific target tissues plays an important role in development and progression of the disease. FTY720 almost completely inhibits joint destruction as well as paw edema in adjuvant-induced arthritis and type II collagen-induced arthritis in LEW rats [13,74]. Recently, It has been reported that FTY720 suppressed the progression of arthritis in SKG mice [75]. FTY720 treatment decreased bone destruction, IL-6 and tumor necrosis factor (TNF)-α expression in synovial fibroblast cells, and the in filtration of inflammatory cells. The analyses of the underlying mechanisms revealed that FTY720 can inhibit arthritis in SKG mice via sequestration of autoimmune CD4 T cells in the SLO, enhancement of helper T cell type 2 (Th2) immune responses, and inhibition of prostaglandin E2 production by synovial cells. Moreover, we also found that FTY720 showed marked prophylactic and therapeutic effects on type II collagen-induced arthritis in DBA/1J mice; with a significant reduction in CD4 T cell infiltration into the arthritic joints and anti-type II collagen antibodies in plasma. Interestingly, FTY720 in combination with anti-murine TNF-α monoclonal antibody showed a synergistic effect on collagen-induced arthritis in DBA/1J mice. These data suggest that FTY720 has a therapeutic potential for RA.
It has been demonstrated that FTY720 shows a marked therapeutic effect on lupus nephritis in animal models for SLE: autoimmune MRL/lpr mice [12,76,77] and NZB/W F1 mice [78]. FTY720 significantly suppressed the production of anti-double stranded (ds) DNA antibodies, reduced the deposition of IgG in glomeruli, and prolonged the lifespan of female MRL/lpr mice. Moreover, it has been demonstrated that KRP-203, a more selective S1P1 agonist attenuates kidney injury and prolongs survival in MRL/lpr mice by reducing T cell infiltration [77]. In aged female NZB/W F1 mice FTY720 reduced proteinuria and ameliorated histological lesions, but did not affect mesangial expansion or the levels of serum anti-dsDNA antibodies [78]. As FTY720 produces great improvement in murine lupus nephritis models, FTY720 seems to have promising therapeutic potential in human SLE.
There are several reports on the therapeutic effects of FTY720 on IBD models [79,80,81,82]. Therapeutic administration of FTY720 ameliorated the chronic colitis in an IL-10 gene-deficient mouse and this effect is probably due to reduction of lymphocyte infiltration in the colonic mucosa with reduction in IFN-γ production [79]. FTY720 prevented the infiltration of CD4 T cells into the inflamed colonic lamina propria and attenuated the development of dextran sulfate sodium-induced colitis and CD4+ CD62L+ T cell transfer colitis in mice [80]. In a mouse colitis model induced by 2,4, 6-trinitrobenzene sulfonic acid (TNBS), FTY720 shows significant therapeutic effects with a down-regulation of Th1 cytokines [81,82]. Specifically, FTY720 treatment results in up-regulation of FoxP3, IL-10, transforming growth factor (TGF)-β, and CTLA4, suggesting down-regulation of pro-inflammatory signals by inducing CD4+ CD25+ regulatory T cells [81].
As shown in Figure 5, FTY720 shows significant therapeutic effects on type II collagen-induced arthritis in DBA/1 mice as well as lupus nephritis in aged MRL/lpr mice. In both autoimmune disease models, significant amounts of CD4 T cells are found to be infiltrated into the inflammatory sites. FTY720 treatment markedly reduces the infiltration of CD4 T cells into arthritic joints or lupus kidneys. These results strongly suggest that FTY720 shows therapeutic effects on arthritis and lupus nephritis by reducing lymphocyte trafficking to the inflammatory sites. Based on these findings, it is presumed that FTY720 can provide a new therapeutic approach not only for MS but also for other autoimmune diseases such as RA, SLE, and IBD.
Figure 5. Therapeutic effects of FTY720 on collagen-induced arthritis and lupus nephritis in mice. (A) Arthritis scores of type II collagen-induced arthritis in DBA/1J mice (n =8). FTY720 was given orally for 8 weeks from 8 to 16 weeks after immunization. (B) Immunohistochemical staining of CD4 T cells in the joints. (C) Proteinuria scores in MRL/lpr mice (n = 10). FTY720 was administered orally from 16 to 20 weeks of age. (D) Immunohistochemical staining of CD4 T cells in the kidneys. **: p < 0.01, **: p < 0.05 (Dunnett’s multi-comparison test).
The phase1clinical studies of FTY20 were performed in stable renal transplant patients maintained on a regimen of CsA and corticosteroids [83,84,85], because FTY720 showed a powerful immunosuppressive activity in various experimental allograft models [9,10,11,12]. The administration of single oral doses of FTY720 (0.25 to 3.5 mg/man) caused a dose-dependent reduction in peripheral blood lymphocytes in the stable renal transplant patients [83]. In the phase 1study on pharmacodynamics, pharmacokinetics, and safety of multiple FTY720 doses in stable renal transplant patients, FTY720 significantly reduced the number of PBLby 85%, which reversed within several weeks after the discontinuation of the medication [84,85]. This dose-dependent reduction of the number of PBL by FTY720 in the human strongly suggests sequestration of circulating lymphocytes into the SLO. Atransient reduction of heart rate was observed in the phase 1 studies of FTY720; however FTY720 subjects showed no major increase in adverse events or changes in renal function as compared with placebo-treated patients [84,85]. Pharmacokinetic measurements revealed that FTY720 displayed a linear relationship between doses and blood concentrations [83,84,85].
MS is a common, and often debilitating, autoimmune disease of the CNS. Early active MS lesions are characterized by the presence of infiltrated mononuclear cells around venules and small veins, followed by myelin breakdown and astrogliosis, resulting in irreversible disability. The etiology of MS remains unknown, but is widely considered to involve myelin-specific autoimmune destruction mediated by autoreactive T cells [86,87]. IFN-β, cyclophosphamide, or glatiramer acetate is used for MS therapy [88,89].
The first clinical evidence that FTY720 has therapeutic benefits in MS was provided in a 6-month, placebo-controlled Phase 2 trial involving 281 patients with relapsing MS [90]. Patients who received FTY720 at an oral dose of 1.25 mg or 5.0 mg daily had a significantly lower median total number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) than those who received the placebo. The annualized relapse rates in groups given 1.25 mg and 5.0 mg of FTY720 were 0.35 and 0.36, respectively and were significantly lower than that in the placebo group (0.77). In FTY720-treated MS patients, the number of IL-17-expressing CD4 T cells wasreduced by > 95% in the peripheral blood suggesting tha t FTY720 inhibits egress of Th17 cells from the SLO [71,91]. FTY720 primarily reduced the numbers of CCR7+ CD45RA+ naïve T cells and CCR7+ CD45RA− central memory T cells in the blood in MS patients; whereas CCR7− CD45RA− and CCR7− CD45RA+ effector memory T cell subsets remained in the blood [71,91]. These results suggest that FTY720 effectively inhibits egress of pathogenic Th17 cells from the DLN but doesnot affect the function of effector memory T cells that play an important role in the prevention of systemic infection.
Therapeutic effects of FTY720 wereevaluated in a 24-month Phase 3 FREEDOMS study involving 1, 272 patients with relapsing remitting MS [92]. The patients were randomized to receive a daily oral dose of the placebo or FTY720 at 0.5 mg or 1.25 mg. The annualized relapse rates in groups given 0.5 mg and 1.25 mg of FTY720 were 0.18 and 0.16, respectively and were significantly lower than that in the placebo group (0.40). FTY720 at 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over 24-month period. The cumulative probability of disability progression confirmed after 3 months was 17.7% with 0.5 mg FTY720, 16.6% with 1.25 mg FTY720, and 24.1% with the placebo. FTY720 at 0.5 mg and 1.25 mg showed improved effects compared with placebo in regards to the MRI-related measures. Similar results of FTY720 were obtained during the Phase 2 study in Japanese relapsing MS patients [93,94]. Moreover, therapeutic effects of FTY720 were directly compared with IFN-β-1a in a 12-month Phase 3 TRANSFORMS study involving 1, 292 patients with relapsing remitting MS [95]. Patients were randomized to receive a daily oral dose of 0.5 mg or 1.25 mg FTY720, or a weekly intramuscular injection of IFN-β-1a. The annualized relapse rates in groups given FTY720 0.5 mg and 1.25 mg were 0.16 and 0.20, respectively, and were significantly lower than in the group receiving IFN-β-1a (0.33).Based on these data, FTY720 (Gilenya®/Imusera®) has been approved as a new therapeutic drug for treatment of MS in more than 75countries including US, EU, and Japan.
The other Phase 3 clinical trials of FTY720 are now ongoing in primary progressive MS patients and in chronic inflammatory demyelinating polyneuropathy (CIDP) patients. Recently it has been reported that FTY720 increases brain-derived neurotrophic factor (BDNF) levels and improves symptoms of a mouse model of Rett syndrome: mice lacking Mecp2, a gene frequently mutated in Rett syndrome [96]. Since FTY720 may improve the functional output of the nervous system, in addition to its well-documented effects on lymphocyte egress from lymph nodes, several investigational clinical studies of FTY720 may be started or conducted in Rett syndrome or other diseases in the CNS.
FTY720-P acts as a functional antagonist at lymphocytic S1P1 and inhibits lymphocyte egress from the SLO. Additionally, FTY720 decreases the infiltration of autoreactive T cells into inflammatory sites, thereby exerting powerful immunosuppressive activity. There are some possibilities for S1P1 functional antagonism in non-lymphoid cells in the pharmacological effects of FTY720 because S1P1 is highly expressed in not only lymphocytes but also endothelial cells and neural cells. The mild increases in blood pressure observed in the FTY720 clinical trials may relate to a down-modulation of S1P1 in vascular endothelium [41] which could reduce activation of the vasodilatory endothelial nitric oxide synthetase pathway by endogenous S1P [65,97]. Therefore, it is thought that blocking of the S1P-S1P1 axis in endothelial cells may be useful for cancer therapies because S1P can promote angiogenesis via S1P1.
Since studies in S1P3-deficient mice suggested a major role for S1P3 in heart rate regulation [98], a number of FTY720 analogues having the 2-aminopropane-1, 3-diol framework or a more simplified 2-aminoethanol framework were synthesized [99,100]. The phosphorylated form of KRP-203 was reported to show no affinity to the S1P3 and is expected to be safer than FTY720 [99]. Although KRP-203 was evaluated in phase 2 clinical trials in IBD, until now, there have been no reports on the efficacy and safety of this compound in human studies.
Some selective chemical probes have been designed and synthesized to elucidate the biological function and physiological role of S1P receptors. [101,102,103,104]. These compounds are non-prodrug type S1P receptor agonists and are believed to bind to the S1P receptors directly. Among them, siponimod (BAF312) is thought to be a next-generation S1P receptor modulator, because this compound is an oral selective modulator for S1P1 and S1P5 [105,106,107,108]. The effects of siponimod on brain MRI lesion activity, safety, and tolerability were examined in double-blind, adaptive dose-ranging phase 2 clinical trials in patients with relapsing remitting MS [108]. Siponimod (0.25 to 10 mg/man) reduced the number of active lesions in a dose-dependent manner, indicating therapeutic effects on MS and the P3 clinical trials are now ongoing. Ponesimod, another selective S1P receptor selective for S1P1 and S1P5, is reported to show significant therapeutic effects in the phase 2 clinical trials in not only relapsing remitting MS [109] but also in chronic plaque psoriasis patients [110], indicating an extensive possibility of S1P1 functional antagonists to the therapy for peripheral autoimmune diseases.
Notably, like FTY720, siponimod and ponesimod also showed a transient reduction of heart rate, however these compounds are more selective for S1P1 and have no affinity at S1P3. It is thought that the transient reduction of heart rate observed in FTY720 clinical trials may relate to S1P1-dependent activation of the G protein-coupled inwardly rectifying potassium (GIRK) channels in cardiomyocytes, prior to internalization of the S1P1 by FTY720 [71]. Furthermore, it is reported that S1P1 is expressed strongly whereas S1P3 is only weakly expressed in human cardiomyocytes, suggesting species differences [111]. Because no differences were observed among FTY720 and clinically developing S1P modulators in down-regulation and degradation of S1P1 receptor [112], it can be concluded that the approach of elimination of S1P3 affinity to avoid the transient reduction of heart rate which was observed in FTY720 treatment is considerably difficult.
FTY720 and selective S1P receptor modulators are highly efficacious in MS patients; however dose-dependent increases in adverse events have tempered its utility. It has been demonstrated that FTY720-P induces phosphorylation of the C-terminal domain of S1P1 at multiple sites, resulting in S1P1 internalization, polyubiquitinylation, and degradation [113]. Although the ubiquitin E3 ligase WWP2 plays an important role in degradation of S1P1 by FTY720-P, it is likely that the degradation of S1P1 is not essential for the decrease in the number of PBL, but is critical for pulmonary vascular leak in vivo. Prevention of phosphorylation, internalization, and degradation of S1P1 inhibited vascular leak, suggesting that discrete mechanisms of S1P1 regulation are responsible for the efficacy and adverse events associated with this class of therapeutics. The concept of ligand bias, whereby a ligand stabilizes subsets of receptor conformations to engender novel pharmacological profiles, has recently gained increasing prominence [114]. Consequently, a biased ligand for S1P1 may deliver safer, better tolerated, and more efficacious drugs.
FTY720 is a first-in-class S1P1 functional antagonist which was discovered by chemical modification of a natural product. Throughout the analyses of the molecular mechanism of FTY720, it has been highlighted that the S1P-S1P1 axis plays an important role in lymphocyte egress from the SLO and thymus. FTY720-Pinduces down-regulation of lymphocytic S1P1 and inhibits egress of lymphocytes including autoreactive Th17 and Th1 cells from the SLO. Recently, it has been suggested that FTY720-P acts directly as a functional antagonist at S1P1 on astrocytesto attenuate neuroinflammation. In relapsing remitting MS patients, oral FTY720 has shown superior efficacy when compared to intramuscular IFN-β-1a in regards to reducing the rate of relapse and the number of inflammatory lesions in the CNS. Based on these data, S1P1 functional antagonists including FTY720 appear to provide a useful therapeutic approach for MS, an autoimmune disease in the CNS. In other chronic autoimmune diseases such as RA, SLE, and IBD, it is highly probable that the S1P-S1P1 axis plays an important role in the trafficking and infiltration of autoreactive lymphocytes in specific target tissues. Consequently, S1P1 functional antagonists may become efficacious and beneficial therapeutic drugs for these autoimmune diseases.
The authors thank Kunitomo Adachi, Kyoko Shimano, Noriko Sato, Kana Takemoto, Hiroyuki Utsumi, Atsushi Fukunari, and Yukio Hoshinoin Mitsubishi Tanabe Pharma Corporation for their fruitful collaborations throughout the research.
The authors declare that there are no conflicts of interest related to this study.
| [1] | Fujita T, Inoue K, Yamamoto S, et al. (1994) Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot 47: 208-215. |
| [2] | Fujita T, Inoue K, Yamamoto S, et al. (1994) Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyruiocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2- hydroxy- methyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives. J Antibiot 47: 216-224. |
| [3] |
Fujita T, Yoneta M, Hirose R, et al. (1995) Simple compounds, 2-alkyl-2- amino-1,3-propane-diols have potent immunosuppressive activity. Bioorg Med Chem Lett 5: 847-852. doi: 10.1016/0960-894X(95)00126-E
|
| [4] |
Adachi K, Kohara T, Nakao N, et al. (1995) Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immuno- suppressant, FTY720. Bioorg Med Chem Lett 5: 853-856. doi: 10.1016/0960-894X(95)00127-F
|
| [5] |
Fujita T, Hirose R, Yoneta M, et al. (1996) Potent immunosuppressants, 2-alkyl-2- aminopropane-1,3-diols. J Med Chem 39: 4451-4459. doi: 10.1021/jm960391l
|
| [6] |
Kiuchi M, Adachi K, Kohara T, et al. (2000) Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J Med Chem 43: 2946-2961. doi: 10.1021/jm000173z
|
| [7] | Adachi K, Chiba K (2008) FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect Medicin Chem 1: 11-23. |
| [8] |
Chiba K, Adachi K (2012) Sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis. Pharmaceuticals 5:514-528. doi: 10.3390/ph5050514
|
| [9] | Chiba K, Hoshino Y, Suzuki C, et al. (1996) FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant Proc 28: 1056-1059. |
| [10] | Hoshino Y, Suzuki C, Ohtsuki M, et al. (1996) FTY720, a novel immunosuppressant possessing unique mechanisms. II. Long-term graft survival induction in rat heterotopic cardiac allografts and synergistic effect in combination with cyclosporine A. Transplant Proc 28: 1060-1061. |
| [11] | Kawaguchi T, Hoshino Y, Rahman F, et al. (1996) FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporine A. Transplant Proc 28: 1062-1063. |
| [12] |
Chiba K. (2005) FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 108: 308-319. doi: 10.1016/j.pharmthera.2005.05.002
|
| [13] |
Matsuura M, Imayoshi T, Chiba K, Okumoto T (2000) Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats. Inflamm Res 49: 404-410. doi: 10.1007/s000110050608
|
| [14] | Chiba K, Yanagawa Y, Masubuchi Y, et al. (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 160: 5037-5044. |
| [15] | Yanagawa Y, Sugahara K, Kataoka H, et al. (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol 160: 5493-5499. |
| [16] |
Brinkmann V. Pinschewer D, Chiba K, Feng L (2000) FTY720: A novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci 21: 49-52. doi: 10.1016/S0165-6147(99)01419-4
|
| [17] |
Brinkmann V, Davis MD, Heise CE, et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277: 21453-21457. doi: 10.1074/jbc.C200176200
|
| [18] |
Mandala S, Hajdu R, Bergstrom J, et al. (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296: 346-349. doi: 10.1126/science.1070238
|
| [19] |
Matloubian M, Lo CG, Cinamon G, et al. (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427: 355-360. doi: 10.1038/nature02284
|
| [20] |
Spiegel S, Milstien S (2007) Functions of the multifaceted family od sphingosine kinases and some dose relatives. J Biol Chem 282: 2125-2129. doi: 10.1074/jbc.R600028200
|
| [21] |
Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9: 139-150. doi: 10.1038/nrm2329
|
| [22] |
Pyne S, Pyne N (2000) Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol Ther 88: 115-131. doi: 10.1016/S0163-7258(00)00084-X
|
| [23] | Spiegel S (2000) Sphingosine 1-phosphate: A ligand for the EDG-1 family of G-protein-coupled receptors. Ann NY Acad Sci 905: 54-60. |
| [24] |
Rivera J, Proia RL, Olivera A (2008) The alliance of shpingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8: 753-763. doi: 10.1038/nri2400
|
| [25] |
Spiegel S, Milstien S (2011) The outs and the ins of shingosine-1-phosphate in immunity. Nat Rev Immunol 11: 403-415. doi: 10.1038/nri2974
|
| [26] |
Paugh SW, Payne SG, Barbour SE, et al. (2003) The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 554:189-193. doi: 10.1016/S0014-5793(03)01168-2
|
| [27] | Chiba K, Matsuyuki H, Maeda Y, Sugahara K (2006) Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol 3: 11-19. |
| [28] |
Maeda Y, Matsuyuki H, Shimano K, et al. (2007) Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J Immunol 178: 3437-3446. doi: 10.4049/jimmunol.178.6.3437
|
| [29] |
Pham TH, Okada T, Matloubian M, et al. (2008) S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity 28: 122-133. doi: 10.1016/j.immuni.2007.11.017
|
| [30] |
Cyster JG (2005) Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 23: 127-159. doi: 10.1146/annurev.immunol.23.021704.115628
|
| [31] |
Mitra P, Oskeritzian CA, Payne SG, et al. (2006) Role of ABCC1 in export of sphingosine- 1-phosphate from mast cells. Proc Natl Acad Sci USA 103: 16394-16399. doi: 10.1073/pnas.0603734103
|
| [32] |
Nishi T, Kobayashi N, Hisano Y et al. (2014) Molecular and physiological functions of sphingosine 1-phosphate transporters. Biochim Biophys Acta 1841: 759-765. doi: 10.1016/j.bbalip.2013.07.012
|
| [33] |
Mechtcheriakova D, Wlachos A, Sobanov J, et al. (2007) Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses. Cell Signal 19: 748-760. doi: 10.1016/j.cellsig.2006.09.004
|
| [34] |
Peest U, Sensken SC, Andréani P, et al. (2008) S1P-lyase independent clearance of extracellular sphingosine 1-phosphate after dephosphorylation and cellular uptake. J Cell Biochem 104: 756-772. doi: 10.1002/jcb.21665
|
| [35] |
Zhao Y, Kalari SK, Usatyuk PV, et al. (2007) Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: role of lipid phosphate phosphatase-1 and sphingosine kinase 1. J Biol Chem 282: 14165-14177. doi: 10.1074/jbc.M701279200
|
| [36] |
Pappu R, Schwab SR, Cornelissen I, et al. (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316: 295-298. doi: 10.1126/science.1139221
|
| [37] |
Schwab SR, Pereira JP, Matloubian M, et al. (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309: 1735-1739. doi: 10.1126/science.1113640
|
| [38] |
Lo CG, Xu Y, Proia RL, Cyster JG (2005) Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med. 201: 291-301. doi: 10.1084/jem.20041509
|
| [39] |
Kiuchi M, Adachi K, Tomatsu A, et al. (2005) Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate. Bioorg. Med. Chem 13: 425-432. doi: 10.1016/j.bmc.2004.10.008
|
| [40] | Matsuyuki H, Maeda Y, Yano K, et al. (2006) Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell Mol Immunol 3: 429-437. |
| [41] |
Oo ML, Thangada S, Wu MT, et al. (2007) Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem 282: 9082-9089. doi: 10.1074/jbc.M610318200
|
| [42] |
Ladi E, Yin X, Chtanova T, Robey EA (2006) Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7: 338-343. doi: 10.1038/ni1323
|
| [43] |
Drennan MB, Elewaut D, Hogquist KA (2009) Thymic emigration: sphingosine-1-phosphate receptor-1-dependent models and beyond. Eur J Immunol 39: 925-930. doi: 10.1002/eji.200838912
|
| [44] | Kato S, Schoefl GI (1989) Microvasculature of normal and involuted mouse thymus. Light- and electron-microscopic study. Acta Anat (Basel) 135: 1-11. |
| [45] |
Kato S (1997) Thymic microvascular system. Microsc Res Tech 38: 287-299. doi: 10.1002/(SICI)1097-0029(19970801)38:3<287::AID-JEMT9>3.0.CO;2-J
|
| [46] |
Mori K, Itoi M, Tsukamoto N, et al. (2007) The perivascular space as a path of hematopoietic progenitor cells and mature T cells between the blood circulation and the thymic parenchyma. Int Immunol 19: 745-753. doi: 10.1093/intimm/dxm041
|
| [47] |
Zachariah MA, Cyster JG (2010) Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328: 1129-1135. doi: 10.1126/science.1188222
|
| [48] |
Cyster JG, Schwab SR (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30: 69-94. doi: 10.1146/annurev-immunol-020711-075011
|
| [49] | Yagi H, Kamba R, Chiba K, et al. (2000) Immunosuppressant FTY720 inhibits thymocyte emigration. Eur J Immunol 30:1435. |
| [50] |
Maeda Y, Yagi H, Takemoto K, et al. (2014) S1P lyase in thymic perivascular space promotes egress of mature thymocytes via up-regulation of S1P receptor 1. Int Immunol 26: 245-255. doi: 10.1093/intimm/dxt069
|
| [51] |
Allende ML, Dreier JL, Mandala S, Proia RL (2004) Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 279: 15396-15401. doi: 10.1074/jbc.M314291200
|
| [52] |
Saba JD, Hla T (2004) Point-counterpoint of sphingosine 1-phosphate metabolism. Circ Res 94: 724-734. doi: 10.1161/01.RES.0000122383.60368.24
|
| [53] |
Breart B, Ramos-Perez WD, Mendoza A, et al. (2011) Lipid phosphate phosphatase 3 enables efficient thymic egress. J Exp Med 208: 1267-1278. doi: 10.1084/jem.20102551
|
| [54] | Vogel P, Donoviel MS, Read R, et al. (2009) Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions. PLoS One 4:e4112. |
| [55] |
Borowsky AD, Bandhuvula P, Kumar A, , et al. (2012) Sphingosine-1-phosphate lyase expression in embryonic and adult murine tissues. J Lipid Res 53: 1920-1931. doi: 10.1194/jlr.M028084
|
| [56] |
Suzuki S, Li XK, Enosawa S, and Shinomiya T (1996) A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes. Immunology 89:518-23. doi: 10.1046/j.1365-2567.1996.d01-777.x
|
| [57] |
Nagahara Y, Enosawa S, Ikekita M, et al. (2000) Evidence that FTY720 induces T cell apoptosis in vivo. Immunopharmacology 48:75-85. doi: 10.1016/S0162-3109(00)00181-8
|
| [58] |
Luo ZJ, Tanaka T, Kimura F, Miyasaka M (1999) Analysis of the mode of action of a novel immunosuppressant FTY720 in mice. Immunopharmacology. 41:199-207. doi: 10.1016/S0162-3109(99)00004-1
|
| [59] |
Sugito K, Koshinaga T, Inoue M, et al. (2005) The effect of a novel immunosuppressant, FTY720, in mice without secondary lymphoid organs. Surg Today 35:662-7. doi: 10.1007/s00595-005-3011-x
|
| [60] |
Maeda Y, Seki N, Sato N, et al. (2010) Sphingosine 1-phosphate receptor type 1 regulates egress of mature T cells from mouse bone marrow. Int Immunol 22: 515-525. doi: 10.1093/intimm/dxq036
|
| [61] |
Webb M, Tham CS, Lin FF, et al. (2004) Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 153: 108-121. doi: 10.1016/j.jneuroim.2004.04.015
|
| [62] | Kataoka H, Sugahara K, Shimano K, et al. (2005) FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2: 439-448. |
| [63] |
Balatoni B, Storch MK, Swoboda EM, et al. (2007) FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull 74: 307-316. doi: 10.1016/j.brainresbull.2007.06.023
|
| [64] |
Foster CA, Howard LM, Schweitzer A, et al. (2007) Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: Consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther 323: 469-475. doi: 10.1124/jpet.107.127183
|
| [65] |
Brinkmann V (2007) Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 115: 84-105. doi: 10.1016/j.pharmthera.2007.04.006
|
| [66] |
Chiba K, Kataoka H, Seki N, et al. (2011) Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis. Int Immunopharmacol 11: 366-372. doi: 10.1016/j.intimp.2010.10.005
|
| [67] |
Langrish CL, Chen Y, Blumenschein WM, et al. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201: 233-240. doi: 10.1084/jem.20041257
|
| [68] |
Komiyama Y, Nakae S, Matsuki T, et al. (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177: 566-573. doi: 10.4049/jimmunol.177.1.566
|
| [69] |
Stromnes IM, Cerretti LM, Liggitt D, et al. (2008) Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med 14: 337-342. doi: 10.1038/nm1715
|
| [70] | Seki N, Maeda Y, Kataoka H, et al. (2013) Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitis. I. S1P-S1P1 axis induces migration of Th1 and Th17 cells. Pharmacology & Pharmacy 4: 628-637. |
| [71] |
Brinkmann V (2009) FTY720 (fingolimod) in Multiple Sclerosis: Therapeutic effects in the immune and the central nervous system. Br J Pharmacol 158: 1173-1182. doi: 10.1111/j.1476-5381.2009.00451.x
|
| [72] |
Choi JW, Gardell SE, Herr DR, et al. (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA 108: 751-756. doi: 10.1073/pnas.1014154108
|
| [73] | Seki N, Kataoka H, Sugahara K, et al. (2013) Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitis. II. S1P-S1P1 axis induces pro-inflammatory cytokine production in astrocytes. Pharmacology & Pharmacy 4: 638-646. |
| [74] |
Matsuura M, Imayoshi T, Okumoto T (2000) Effect of FTY720, a novel immunosuppressant, on adjuvant- and collagen-induced arthritis in rats. Int J Immunopharmacol 22: 323-331. doi: 10.1016/S0192-0561(99)00088-0
|
| [75] |
Tsunemi S, Iwasaki T, Kitano S, et al. (2010) Effects of the novel immunosuppressant FTY720 in a murine rheumatoid arthritis model. Clin Immunol 136: 197-204. doi: 10.1016/j.clim.2010.03.428
|
| [76] | Okazaki H, Hirata D, Kamimura T, et al. (2002) Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus. J Rheumatol 29: 707-716. |
| [77] |
Wenderfer SE, Stepkowski SM, Braun MC (2008) Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist. Kidney Int 74: 1319-1326. doi: 10.1038/ki.2008.396
|
| [78] |
Alperovich G, Rama I, Lloberas N, et al. (2007) New immunosuppresor strategies in the treatment of murine lupus nephritis. Lupus 16: 18-24. doi: 10.1177/0961203306073136
|
| [79] |
Mizushima T, Ito T, Kishi D, et al. (2004) Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis. Inflamm Bowel Dis 10: 182-192. doi: 10.1097/00054725-200405000-00002
|
| [80] | Deguchi Y, Andoh A, Yagi Y, et al (2006) The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. Oncol Rep 16: 699-703. |
| [81] |
Daniel C, Sartory N, Zahn N, et al. (2007) FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 178: 2458-2468. doi: 10.4049/jimmunol.178.4.2458
|
| [82] |
Radi ZA, Heuvelman DM, Masferrer JL, et al (2011) Pharmacologic evaluation of sulfasalazine, FTY720, and anti-IL-12/23p40 in a TNBS-induced Crohn's disease model. Dig Dis Sci 56: 2283-2291. doi: 10.1007/s10620-011-1628-8
|
| [83] | Budde K, Schmouder RL, Brunkhorst R, et al. (2002) Human first trail of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 13: 1073-1083. |
| [84] |
Budde K, Schmouder RL, Nashan B, et al. (2003) Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant 3: 846-854. doi: 10.1034/j.1600-6143.2003.00130.x
|
| [85] |
Kahan BD, Karlix JL, Ferguson RM, et al. (2003) Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 76: 1079-1084. doi: 10.1097/01.TP.0000084822.01372.AC
|
| [86] |
Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10: 153-187. doi: 10.1146/annurev.iy.10.040192.001101
|
| [87] |
Kornek B, Storch MK, Weissert R, et al. (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: A comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157: 267-276. doi: 10.1016/S0002-9440(10)64537-3
|
| [88] | Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46: 907-911. |
| [89] | Goodkin DE, Reingold S, Sibley W, et al. (1999) Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: Reporting extended results from phase III clinical trials. National Multiple Sclerosis Society Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Ann Neurol 46: 132-134. |
| [90] |
Kappos L, Antel J, Comi G, et al. (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Eng J Med 355: 1124-1140. doi: 10.1056/NEJMoa052643
|
| [91] | Mehling M, Lindberg R, Raulf F, et al. (2011) Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 75: 403-410. |
| [92] |
Kappos L, Radue EW, O’Connor P, et al. (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362: 387-401. doi: 10.1056/NEJMoa0909494
|
| [93] | Saida T, Kikuchi S, Itoyama Y, et al. (2012) A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Mult Scler 18:1267-1277. |
| [94] |
Kira J, Itoyama Y, Kikuchi S, et al. (2014) Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. BMC Neurology 14: 21. doi: 10.1186/1471-2377-14-21
|
| [95] |
Cohen JA, Barkhof F, Comi G, et al. (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362: 402-415. doi: 10.1056/NEJMoa0907839
|
| [96] | Deogracias R, Yazdani M, Dekkers MP, et al (2013) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci USA 109: 14230-14235. |
| [97] |
Igarashi J, Erwin PA, Dantas AP, et al. (2003) VEGF induces S1P1 receptors in endothelial cells: implications for crosstalk between sphingolipid and growth factors receptors. Proc Natl Acad Sci USA 100: 10664-10669. doi: 10.1073/pnas.1934494100
|
| [98] |
Sanna MG, Liao J, Jo E, et al. (2004). Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279: 13839-13848. doi: 10.1074/jbc.M311743200
|
| [99] |
Shimizu H, Takahashi M, T. Kaneko T et al. (2005) KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts. Circulation 111: 222-229. doi: 10.1161/01.CIR.0000152101.41037.AB
|
| [100] |
Hamada M, Nakamura M, Kiuchi M et al. (2010) Removal of sphingosine 1-phosphate receptor-3 (S1P3) agonism is essential, but inadequate to obtain immunomodulating 2-aminopropane-1,3-diol S1P1 agonists with reduced effect on heart rate. J Med Chem 53: 3154-3168. doi: 10.1021/jm901776q
|
| [101] |
Hale JJ, Lynch, CL, Neway WE, et al. (2004) A unique utilization of high throughput screening leads to afford selective, orally bioavailable 1-benzyl-3-carboxyazetidine S1P1 receptor agonists. J Med Chem 47: 6662-6665. doi: 10.1021/jm0492507
|
| [102] |
Vachal P, Toth LM, Hale JJ, et al. (2006) Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor. Bioorg Med Chem Lett 16: 3684-3687. doi: 10.1016/j.bmcl.2006.04.064
|
| [103] | Foss FW, Snyder AH, Davis MD, et al. (2007) Synthesis and biological evaluation of gammma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem 15: 663–677. |
| [104] |
Hanessian S, Charron G, Billich A, et al. (2007) Constrained azacyclic analogues of the immunomodulatory agent FTY720 as molecular probes for sphingosine 1-phosphate receptors. Bioorg Med Chem Lett 17: 491-494. doi: 10.1016/j.bmcl.2006.10.014
|
| [105] |
Pan S, Gray NS, Gao W, et al. (2013) Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett 4: 333-337. doi: 10.1021/ml300396r
|
| [106] |
Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 167: 1035-1047. doi: 10.1111/j.1476-5381.2012.02061.x
|
| [107] |
Selmaj K, Li DK, Hartung HP, et al. (2013) Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 12: 756-767. doi: 10.1016/S1474-4422(13)70102-9
|
| [108] | Biswal S, Veldandi UK, Derne C, et al. (2014) Effect of oral siponimod (BAF312) on the pharmacokinetics and pharmacodynamics of a monophasic oral contraceptive in healthy female subjects. Int J Clin Pharmacol Ther Aug 27. [Epub ahead of print] |
| [109] |
Olsson T, Boster A, Fernández O, et al (2014) Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry 85: 1198-1208. doi: 10.1136/jnnp-2013-307282
|
| [110] | Vaclavkova A, Chimenti S, Arenberger P, et al. (2014) Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet pii: S0140-6736: 60803-60805. |
| [111] |
Mazurais D, Robert P, Gout B, et al. (2002) Cell type-specific localization of human cardiac S1P receptors. J Histochem Cytochem 50: 661-670. doi: 10.1177/002215540205000507
|
| [112] |
Lukas S, Patnaude L, Haxhinasto S, et al. (2014) No differences observed among multiple clinical S1P1 receptor agonists (functional antagonists) in S1P1 receptor down-regulation and degradation. J Biomol Screen 19: 407-416. doi: 10.1177/1087057113502234
|
| [113] |
Oo ML, Chang SH, Thangada S, et al. (2011) Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest 121: 2290-2300. doi: 10.1172/JCI45403
|
| [114] |
Violin JD, Crombie AL, Soergel DG, et al. (2014) Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci 35: 308-316. doi: 10.1016/j.tips.2014.04.007
|
| 1. | Michael J. Genin, Isabel C. Gonzalez Valcarcel, William G. Holloway, Jason Lamar, Marian Mosior, Eric Hawkins, Thomas Estridge, Jeffrey Weidner, Thomas Seng, David Yurek, Lisa A. Adams, Jennifer Weller, Vincent L. Reynolds, Joseph T. Brozinick, Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase, 2016, 59, 0022-2623, 5904, 10.1021/acs.jmedchem.5b01851 | |
| 2. | Martin Braddock, 2015, Chapter 45-1, 978-3-642-27728-3, 1, 10.1007/978-3-642-27728-3_45-1 | |
| 3. | Martin Braddock, 2016, Chapter 45, 978-3-319-05391-2, 2091, 10.1007/978-3-319-05392-9_45 | |
| 4. | Fatma Zehra Okus, Zehra Busra Azizoglu, Halit Canatan, Ahmet Eken, S1P analogues SEW2871, BAF312 and FTY720 affect human Th17 and Treg generation ex vivo, 2022, 107, 15675769, 108665, 10.1016/j.intimp.2022.108665 | |
| 5. | Byunghyun Park, Yu Sun Jeong, Wonseok Hu, Mingyu Lee, Ji Cheol Kim, Geon Ho Bae, Yong-Soo Bae, Yoe-Sik Bae, Sphingosylphosphorylcholine inhibits plasma cell differentiation and ameliorates experimental autoimmune encephalomyelitis, 2023, 14, 1664-3224, 10.3389/fimmu.2023.1151511 | |
| 6. | Ryoji Kise, Asuka Inoue, GPCR signaling bias: an emerging framework for opioid drug development, 2024, 175, 0021-924X, 367, 10.1093/jb/mvae013 | |
| 7. | Martin Braddock, 2024, Chapter 149, 978-3-031-35528-8, 861, 10.1007/978-3-031-35529-5_149 | |
| 8. | Martin Braddock, 2024, Chapter 149-1, 978-3-030-73317-9, 1, 10.1007/978-3-030-73317-9_149-1 |
Figures(5)
Kenji Chiba, Yasuhiro Maeda, Noriyasu Seki, Hirotoshi Kataoka, Kunio Sugahara. Role of sphingosine 1-phosphate (S1P) and effects of fingolimod, an S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases[J]. AIMS Molecular Science, 2014, 1(4): 162-182. doi: 10.3934/molsci.2014.4.162
DownLoad: 